Pharmacokinetics and brain penetration of LF-3-88, (2-5-5-(2(S)-azetidinylmethoxyl)-3-pyridyl-3-isoxazolylethanol, a selective α4β2-nAChRs partial agonist

摘要

Neuronal nicotinic acetylcholine receptors (nAChRs) belong to the ligand- gated ion channel super- family of neurotransmitter receptors, which are widely distributed in both the central and peripheral nervous system. They are pentamers assembled from varying combinations of subunits (α2-α10, β 2-β 4) with a broad range of pharmacological properties. Previous studies have shown that the blockade (antagonism or receptor desensitization) of α4β2- nAChRs result s in antidepressant - like effects. Highly selective α4 β 2- nAChRs partial agonists are regarded as promising antidepressant medications. Compound LF -3-88 (2-[5 - [5 -(2(S) -azetidinylmethoxyl)-3-pyridyl]-3-isoxazolyl]ethanol was identified as a highly selective α4β2- nAChRs partial agonist, with a K_i value of 0.4 nM and EC_(50) value of 110 nM. We developed and validated a UHPLC-MS- MS method for quantitative analysis of LF-3-88 in mouse plasma and brain to support pharmacokinetics studies.